Splicing factor NSSR1 reduces neuronal injury after mouse transient global cerebral ischemia

Glia. 2015 May;63(5):826-45. doi: 10.1002/glia.22787. Epub 2015 Jan 27.


This study focuses on the function of NSSR1, a splicing factor, in neuronal injury in the ischemic mouse brain using the transient global cerebral ischemic mouse model and the cultured cells treated with oxygen-glucose deprivation (OGD). The results showed that the cerebral ischemia triggers the expression of NSSR1 in hippocampal astrocytes, predominantly the dephosphorylated NSSR1 proteins, and the Exon3 inclusive NCAM-L1 variant and the Exon4 inclusive CREB variant. While in the hippocampus of astrocyte-specific NSSR1 conditional knockdown (cKD) mice, where cerebral ischemia no longer triggers NSSR1 expression in astrocytes, the expression of Exon3 inclusive NCAM-L1 variant and Exon4 inclusive CREB variant were no longer triggered as well. In addition, the injury of hippocampal neurons was more severe in astrocyte-specific NSSR1 cKD mice compared with in wild-type mice after brain ischemia. Of note, the culture media harvested from the astrocytes with overexpression of NSSR1 or the Exon3 inclusive NCAM-L1 variant, or Exon4 inclusive CREB variant were all able to reduce the neuronal injury induced by OGD. The results provide the evidence demonstrating that: (1) Splicing factor NSSR1 is a new factor involved in reducing ischemic injury. (2) Ischemia induces NSSR1 expression in astrocytes, not in neurons. (3) NSSR1-mediated pathway in astrocytes is required for reducing ischemic neuronal injury. (4) NCAM-L1 and CREB are probably mediators in NSSR1-mediated pathway. In conclusion, our results suggest for the first time that NSSR1 may provide a novel mechanism for reducing neuronal injury after ischemia, probably through regulation on alternative splicing of NCAM-L1 and CREB in astrocytes.

Keywords: CREB; NCAM-L1; alternative splicing; astrocytes; expression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD56 Antigen / genetics
  • CD56 Antigen / metabolism
  • CREB-Binding Protein / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / physiology*
  • Glial Fibrillary Acidic Protein / metabolism
  • Glucose / deficiency
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Hippocampus / pathology*
  • Hypoxia / pathology
  • Immunoprecipitation
  • Ischemic Attack, Transient / pathology*
  • Male
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neuroblastoma / pathology
  • Neurons / metabolism*
  • Phosphorylation / genetics
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*


  • CD56 Antigen
  • Cell Cycle Proteins
  • Fusip1 protein, mouse
  • Glial Fibrillary Acidic Protein
  • Ncam1 protein, mouse
  • Neoplasm Proteins
  • RNA-Binding Proteins
  • Repressor Proteins
  • Green Fluorescent Proteins
  • CREB-Binding Protein
  • Glucose